VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction

Harris E. Blankenship, Kelsey A. Carter, Kevin D. Pham, Nina T. Cassidy, Andrea N. Markiewicz, Michael I. Thellmann, Amanda L. Sharpe, Willard M. Freeman and Michael J. Beckstead ()
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Harris E. Blankenship: Oklahoma Medical Research Foundation
Kelsey A. Carter: Oklahoma Medical Research Foundation
Kevin D. Pham: Oklahoma Medical Research Foundation
Nina T. Cassidy: Oklahoma Medical Research Foundation
Andrea N. Markiewicz: Oklahoma Medical Research Foundation
Michael I. Thellmann: Oklahoma Medical Research Foundation
Amanda L. Sharpe: University of Oklahoma Health Sciences Center
Willard M. Freeman: Oklahoma Medical Research Foundation
Michael J. Beckstead: Oklahoma Medical Research Foundation

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role of midbrain dopamine (DA) neurons in AD using the amyloid + tau-driven 3xTg-AD mouse model. We found deficits in reward-based operant learning in AD mice, suggesting possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing in DA neurons caused by reduced activity of small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents of single patch-clamped DA neurons (Patch-seq) identified up-regulation of the SK channel modulator casein kinase 2 (CK2), which we corroborated by immunohistochemical protein analysis. Pharmacological inhibition of CK2 restored SK channel activity and normal firing patterns in 3xTg-AD mice. These findings identify a mechanism of ion channel dysregulation in VTA DA neurons that could contribute to behavioral abnormalities in AD, paving the way for novel treatment strategies.

Date: 2024
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DOI: 10.1038/s41467-024-53891-1

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